Efficacy of immunotherapy in hepatocellular carcinoma: Does liver disease etiology have a role?

The systemic treatment of hepatocellular carcinoma (HCC) is changing rapidly. After a decade of tyrosine kinase inhibitors (TKIs), as the only therapeutic option for the treatment of advanced HCC, in the last few years several phase III trials demonstrated the efficacy of immune checkpoint inhibitors (ICIs). The combination of the anti-PD-L1 atezolizumab and the anti-vascular endothelial growth factor (VEGF) bevacizumab demonstrated the superiority over sorafenib and currently represents the standard of care treatment for advanced HCC. In addition, the combination of durvalumab (an anti-PD-L1) and tremelimumab (an anti-CTLA4) proved to be superior to sorafenib, and in the same trial durvalumab monotherapy showed non-inferiority compared to sorafenib. However, early reports suggest an influence of HCC etiology in modulating the response to these drugs. In particular, a lower effectiveness of ICIs has been suggested in patients with non-viral HCC (in particular non-alcoholic fatty liver disease). Nevertheless, randomized controlled trials available to date have not been stratified for etiology and data suggesting a possible impact of etiology in the outcome of patients managed with ICIs derive from subgroup not pre-specified analyses. In this review, we aim to examine the potential impact of HCC etiology on the response to immunotherapy regimens for HCC.

Physiopathology of nonalcoholic fatty liver disease: from diet to nutrigenomics.

PURPOSE OF REVIEW: Nonalcoholic fatty liver disease (NAFLD) is the most common cause of chronic liver disease worldwide and is strongly associated with metabolic disorders, such as obesity, type 2 diabetes mellitus, and metabolic syndrome, to the extent that a new definition of metabolic associated fatty liver disease has been proposed. RECENT FINDINGS: Insulin resistance, worsened by a high-fat and high-carbohydrate diet, is the key to the physiopathology of hepatic steatosis. This is driven by several mechanisms that are mostly activated at a genetic level, such as de-novo lipogenesis and triglyceride synthesis. Therefore, many diet regimens have been studied, although significant controversies remain regarding their metabolic effects and long-term sustainability. SUMMARY: In this review, we summarized the role and effects of the main macronutrients on the development of NAFLD and discussed the molecular mechanisms involved. We also discussed the importance of genetic polymorphisms, epigenetic alterations, and dysbiosis to determine if lifestyle modification and a specific dietary regimen could be an essential part of NAFLD treatment.